Dimitrios Zardavas and Debora Fumagalli, Breast International Group; Christos Sotiriou, Université Libre de Bruxelles, Brussels, Belgium; Luc te Marvelde and Roger L. Milne, Cancer Council; Roger L. Milne and Sherene Loi, University of Melbourne, Melbourne; Barry Iacopetta, University of Western Australia, Western Australia; Sandra O'Toole and Elena Lopez-Knowles, Garvan Institute of Medical Research, Darlinghurst, Australia; George Fountzilas and Vassiliki Kotoula, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki; Evangelia Razis, Hygeia Hospital; George Papaxoinis, Hippokration Hospital, Athens, Greece; Heikki Joensuu, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Mary Ellen Moynahan, Memorial Sloan Kettering Cancer Center, New York, NY; Bryan T. Hennessy, Beaumont Hospital and Royal College of Surgeons, Dublin, Ireland; Ivan Bieche, Curie Institut, Paris; Thomas Bachelot, Centre de Recherche en Cancérologie de Lyon, Lyon; Stefan Michiels, Gustave Roussy and Inserm, Univ. Paris-Sud, Univ. Paris-Saclay, Villejuif, France; Lao H. Saal, Lund University, Lund; Olle Stal, Qing Wang, and Gizeh Perez-Tenorio, Linköping University, Linköping, Sweden; Jeanette Dupont Jensen, University of Southern Denmark, on behalf of the Danish Breast Cancer Cooperative Group, Odense, Denmark; Elena Lopez-Knowles, Royal Marsden NHS Trust and Institute of Cancer Research, London; Daniel W. Rea, University of Birmingham, Birmingham, United Kingdom; Mattia Barbaraeschi, Santa Chiara Hospital, Trento, Italy; Shinzaburo Noguchi, Osaka University, Osaka Japan; Hatem A. Azim Jr, American University of Beirut (AUB), Beirut, Lebanon; Enrique Lerma, Universitat Autònoma de Barcelona, Barcelona, Spain; Cornelis J.H. can de Velde, Leiden University Medical Center, Leiden, the Netherlands; Vicky Sabine, University of Guelph, Guelph; John M.S. Bartlett, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
J Clin Oncol. 2018 Apr 1;36(10):981-990. doi: 10.1200/JCO.2017.74.8301. Epub 2018 Feb 22.
Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
目的磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚单位α（PIK3CA）突变在原发性乳腺癌中经常发生。我们通过对个体患者数据进行汇总分析来评估其预后相关性。
方法通过应用 Cox 回归模型，根据年龄、肿瘤大小、淋巴结、分级、雌激素受体（ER）状态、人表皮生长因子受体 2（HER2）状态、治疗和研究对 PIK3CA 状态与临床病理特征之间的关系进行了测试。无侵袭性疾病生存（IDFS）是主要终点；还评估了远处无病生存（DDFS）和总生存（OS），包括乳腺癌亚型。
结果纳入了来自 19 项研究的 10319 名患者的数据（中位 OS 随访时间为 6.9 年）；1787 名患者（17%）接受化疗，4036 名（39%）接受内分泌单药治疗，3583 名（35%）同时接受两种治疗，913 名（9%）未接受或其治疗方法未知。32%的患者发生 PIK3CA 突变，与 ER 阳性、年龄增长、分级降低和肿瘤体积较小具有显著相关性（均 P <.001）。在 ER 阴性/HER2 阴性、HER2 阳性和 ER 阳性/HER2 阴性亚型中，PIK3CA 突变的发生率分别为 18%、22%和 37%。单变量分析显示，PIK3CA 突变与更好的 IDFS 相关（HR，0.77；95%CI，0.71 至 0.84；P <.001），在随访的前几年具有更强的作用（0 至 5 年：HR，0.73；95%CI，0.66 至 0.81；P <.001；5 至 10 年：HR，0.82；95%CI，0.68 至 0.99；P =.037）；超过 10 年：（HR，1.15；95%CI，0.84 至 1.58；P =.38；P 异质性=.02）。多变量分析显示，PIK3CA 基因型与 IDFS 改善仍然显著相关（P =.043），但与 DDFS 和 OS 终点无关。
结论在这项大型汇总分析中，PIK3CA 突变与更好的 IDFS、DDFS 和 OS 显著相关，但在调整其他预后因素后，其预后作用较小。
